Cancer remains a major cause of hospitalization and death every year. From time to time, new formulations of anticancer drugs are available in the market and draw the concern of healthcare professionals in terms of the superiority, toxicology, and cost-effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, which is a highly potent chemotherapeutic agent, comes with three formulations (pegylated liposomal, nonpegylated liposomal and nonliposomal conventional formulations). English-language literature in relation to the three formulations has been reviewed to inform the healthcare professionals regarding the differences between these formulations. In terms of efficacy, there is only one study supporting the superiority of liposomal doxorubicin, but there are more data which supports the non-inferiority of liposomal doxorubicin in comparison to conventional non-liposomal doxorubicin. It is emphasized that liposomal doxorubicin promotes better toxicology profile than nonliposomal conventional doxorubicin with an increased cost. The cost-effectiveness of liposomal doxorubicin is not well defined as there are very limited studies in this area. Apart from that, this review highlights the interpatient variability in regards to the clearance and volume of distribution following the administration of liposomal doxorubicin. In conclusion, further studies will be required to better define the superiority of liposomal formulation of doxorubicin regarding the efficacy and dose standardization of liposomal doxorubicin should be sought in the near future.

Keywords: Cancer, doxorubicin, liposome

How to cite this article:Ngan YH, Gupta M. A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated review. Arch Pharma Pract 2016;7:1-13

How to cite this URL:Ngan YH, Gupta M. A comparison between liposomal and nonliposomal formulations of doxorubicin in the treatment of cancer: An updated review. Arch Pharma Pract [serial online] 2016 [cited 2019 Sep 15];7:1-13. Available from: http://www.archivepp.com/text.asp?2016/7/1/1/174930

Introduction

Cancer, which is associated with the rapid and uncontrolled proliferation of cells, is a leading cause of death worldwide. In 2015, it is estimated that there will be 1,658,370 new cases of cancer and account for 589,430 death around the world. [1] There are three distinct approaches to the treatment of cancer, which includes surgical excision, irradiation, and drug therapy. [1],[2] In terms of drug therapy, side effects are almost inevitable and are a common cause of therapeutic limitation. [2]

Doxorubicin is a very potent cytotoxic anticancer that directly inhibits topoisomerase II and nucleic acid synthesis. [3] As a result, the proliferation of cancer cells will be terminated. However, anticancer treatment of doxorubicin is always limited by its severe side effects such as cardiotoxicity like as dysrhythmia and heart failure. [3] Fortunately, this limitation could be resolved through the clinical application of liposomes. [2],[3],[4]

Liposomes are bilayered phospholipid vesicles with an aqueous core that can encapsulate both hydrophilic and hydrophobic drugs. [2] In fact, liposomes can retain the drugs until being disrupted, indicating that they can promote sustained release formulation of drugs. [1],[2],[3],[4] Besides, they are also concentrated in malignant tumors, so that enhance the selectivity of the anticancer drugs with reduced toxicity. [2],[3],[4]

There are several liposomal formulations of anticancer drugs authorized by United State Food and Drug Administration including doxorubicin. [2] A long-acting form of doxorubicin encapsulated in liposomes has been marketed since the mid-1990s for the treatment of various malignancies. [2],[3],[4] It is also known as Doxil in the USA or Caelyx in Europe. [2] This liposomal formulation contains polyethylene glycol (PEG) coated-liposomal doxorubicin, which is capable of targeting doxorubicin to tumor sites. In the present, liposomal doxorubicin is a therapeutic option in the treatment of AIDS-related Kaposi's sarcoma, metastatic breast cancer, advanced ovarian cancer, and relapsed/refractory multiple myelomas. [5]

To investigate the differences among the formulations of doxorubicin invivo, a literature search is conducted. It is hypothesized that liposomal doxorubicin encompasses increased efficacy and better toxicology profile compared to nonliposomal conventional doxorubicin.

Pharmacological Action Of Doxorubicin

Although the exact mode of action remains unknown, the potency of doxorubicin is believed to be associated with topoisomerase II, which is a DNA gyrase and is responsible for the relaxation of supercoiled structure of DNA during transcription. [2],[3] Specifically, doxorubicin intercalates in the DNA and stabilizes the DNA-topoisomerase II complex during the transcription process thus prevents the relaxation of the DNA double helix and promotes termination of the process.

Nevertheless, therapeutic limitations of doxorubicin involve severe adverse effects such as dysrhythmia, heart failure, leukocytopenia, moderate to severe nausea, and vomiting and hemorrhage. [2],[3],[4] Its cardiotoxicity such as dysrhythmia and heart failure arises from the formation of cytotoxic free radicals in the heart tissue. [2],[3],[4] Therefore, this problem can be resolved by increasing the specificity of doxorubicin through the utilization of liposomes. [2],[3],[4]

Clinical Application Of Liposomes In Chemotherapy Of Cancer

Liposomes feature an aqueous core, one or more phospholipid membranes with/without coating groups on the surfaces of the membranes. [2],[3] These amphiphilic characteristics allow liposomes to carry both hydrophobic and hydrophilic drugs within the lipophilic bilayer or aqueous compartment. [2] For instance, hydrophilic drugs dissolve in the aqueous core or adsorb on the hydrophilic head of the phospholipid bilayer whereas lipophilic drugs are filled with the hydrophobic tails of the bilayer. [2],[3],[4],[5],[6]

There are numerous liposome-based anticancer agents being marketed as a liposomal preparation, which are commonly known as Caelyx/Doxil, Myocet, DOX-SL, Lipo-Dox, and DaunoXome. Myocet, Caelyx/Doxil, Liposomal Doxorubicin SUN, and Lipo-Dox are liposomal formulations of doxorubicin whereas DaunoXome is the liposomal formulation of Daunorubicin. [2],[3],[6]

Liposomal Formulation Of Doxorubicin

Specifically, the liposome formulated in Caelyx/Doxil is a type of small unilamellar vesicles (SUV), which is a type of liposomes with a single bilayer and is 30-100 nm in size. [2],[3],[6] Apart from that, the liposome in the formulation is coated with a hydrophilic polymer, PEG, indicating that it is able to escape from mononuclear phagocytic system uptake and to target the tumor cells through the enhanced permeability and retention effect. [2],[6] Doxorubicin in the formulation is manifested in a form of doxorubicin sulfate complex and is covered in the aqueous core of liposome. [2],[3]

The main difference between Lipo-Dox and Caelyx/Doxil is the type of liposome being used. The lipid membrane of Caelyx/Doxil is made of hydrogenated soybean phosphatidylcholine and coated with PEG-distearoylphosphatidylethanolamine (HSPC/PEG-DPSE) whereas the membrane of Lipo-Dox is made of distearoylphosphatidylcholine (DSPC) coated with the same coating material PEG-DSPE. [6] Since DSPC has a higher transition temperature than HSPC, Lipo-Dox offers higher stability and longer half-life compared to Caelyx/Doxil. [6]

Liposomal Doxorubicin SUN contains a liposome coated with sodium methoxy PEG-40-carbonyl-DPSE. [4] Although its coating material is different to Caelyx/Doxil, it is proven to be therapeutically equivalent to Caelyx/Doxil. [5]

Myocet is a type of non-pegylated liposomal doxorubicin (non-PLD) composed of SUV. Similar to Caelyx/Doxil, doxorubicin is located within the aqueous core of the liposome but is manifested in a form of doxorubicin citrate complex. [2],[5]

Literature Review

Data sources and selection

In respect of research strategies, a search of PubMed, Cochrane Library, and EMBASE using the MeSH search terms doxorubicin, liposome, and cancer was performed. Additional search terms are the brand name of doxorubicin which includes DOX-SL, Lipo-Dox, Doxil, Caelyx, Lipo-Dox, and DaunoXome. All articles being reviewed were primary sources and published within the last 5 years (2010-September 2015) except one primary source, which is thought to be vitally important for the quality of life analysis. Apart from that, secondary sources such as textbook, systematic reviews, and meta-analysis were used as a background reference to support the analysis of the primary sources [Table 1].

Table 1: Synopsis of original articles related to liposomal formulation of doxorubicin present in the market

0Large area under the curve (AUC), slow clearance rate (CL), small distribution volume (VD), and long elimination half-time (t½) characterize the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). [8],[9],[22] The VD of PLD is close to the blood volume so that the PK of PLD undergoes single compartment model. [8],[9] The pegylated lipids in the liposomes result in a long circulation half-time, typically 3-4 days. [8],[9]

Nonliposomal conventional doxorubicin has a large VD indicating that a significant amount of the drug is taken up in normal tissues. [8],[22] Apart from that, the AUC for conventional nonliposomal doxorubicin is about three orders of magnitude smaller than PLD resulting in a CL rate about three orders of magnitude larger. The t½ for conventional doxorubicin is about 20-25 h. [8],[9]

Non-PLD has a shorter t½ than PLD but a longer t½ than conventional nonliposomal doxorubicin. [7] It is due to the absence of PEG coating in the formulation, which indicates that it can be easily taken up by the reticuloendothelial system (RES) and undergo metabolism. [5]

Despite the fact that there are imperative benefits associated with PLD and non-PLD than nonliposomal conventional doxorubicin, its interpatient variability in terms of PKs are more clinically significant in comparison to conventional nonliposomal doxorubicin. [8],[9]

Regarding the nonliposomal conventional doxorubicin, factors contributing to interpatient variability are hepatic impairment, patient age and polymorphism in efflux transporter and metabolizing enzymes. [27] Doxorubicin is hepatically cleared by carbonyl reductases (CBR) and cytochrome P-450 enzymes, especially CBR1, CBR3, CYP3A4, CYP2C9, and CYP2D6, which implies that genetic polymorphism of CBR affects the CL of doxorubicin. [27] In relation to that, patients with hepatic impairment as well as elderly population are less capable to metabolize doxorubicin due to their insufficient metabolizing enzymes of doxorubicin. [27] Apart from that, a various subfamily of ATP-binding cassette (ABC) is responsible for pumping out doxorubicin, including ABCB1, ABCB5, ABCB8, ABCC5, and ABCG2. Provided that, polymorphism of the efflux transporter ABC can positively or negatively affect the plasma concentration of doxorubicin. [27]

In comparison to conventional nonliposomal doxorubicin, PLD and non-PLD undertake a more complicated metabolizing pathway. [9] Theoretically, the CL of liposomes depends upon the RES, involving monocytes, macrophages, and dendritic cells. Hence, besides the metabolism of doxorubicin in the aqueous core, the CL of both PLD and non-PLD bears upon the immune system as well as the RES function of different individuals. [8],[9],[22] Deterioration of immunity is common in the aging population, which is scientifically known as immunosenescence. [28] Hence, the CL of doxorubicin in an elderly patient is further reduced which is possible to prolong t½ and AUC of doxorubicin. In spite of the unclear reason, gender is discovered to be an important contributing factor for the CL of liposomal doxorubicin. Clinical significantly, female patients have a lower CL of liposomal doxorubicin than male patient. [8] Although the exact reason for this phenomenon remains unknown, it is thought to be closely associated with the hormone. As hormone plays a key role in the immunosuppressive and immunostimulatory activity, the reason behind this observation can be rationalized. [28] There are many factors contributing to the immune status of individuals, indicating the dramatic interpatient variability of liposomal doxorubicin.

Other factors contributing to interpatient variability of PLD are body fat composition and genetic viability. [12] The phenomenon of significantly increased AUC of PLD as a result of high intraabdominal fat content had been observed. In terms of genetic viability, higher VD and CL rate had been detected in Asian in comparison to European. [16]

Efficacy

The efficacy of the different formulations which involve doxorubicin was evaluated based on response rate, including complete response, partial response, and overall response. The survival rate, which includes overall survival and progression-free survival, is also deemed to be an indicator of efficacy. [6],[7],[10],[13],[22],[24]

The efficacy of PLD as a single agent in the treatment of metastatic breast cancer has been confirmed. However, there is a lack of scientific consensus that the liposomal formulations of doxorubicin increase the survival rate of the treatment, in comparison to nonliposomal conventional doxorubicin. [6],[7],[10],[13],[22],[24] Nevertheless, it is clinically significant that PLD decreases the risk of fatal cardiac events such as acute myocardial infarction and congestive heart failure. [6],[7],[18] As a result, the utilization of PLD increases the survival rate of patients with high cardiac risks compared to nonliposomal conventional doxorubicin. [13],[14]

Despite the efficacy of doxorubicin in the treatment of glioma invitro, its utilization is limited by the efflux effect of the blood-brain barrier (BBB). [15],[22] Fortunately, the development of liposomal doxorubicin allows penetration of doxorubicin into the malignant glioma cells in the brain. [15] In spite of the fact that PLD shows high potency in the treatment of glioma, its dosing regimen in children remains unclear. Hence, further studies are necessary to balance the toxicology profile and efficacy of PLD in the treatment of glioma.

Moreover, there are some discrepancies regarding the potency between two formulations (Lipo-Dox and Doxil) of PLD. [6] An observational study indicates that Lipo-Dox is inferior to Doxil in terms of potency. [6] However, this observation might not be clinically significant as a larger sample size is needed to confirm the finding.

In addition, laboratory data have showed the efficacy of PLD in the treatment of intracranial model of breast cancer in mice. [22] In this model of breast cancer, PLD promotes higher survival rate and efficacy with reduced toxicity than nonliposomal doxorubicin in mice. [22] Clinical data regarding the utilization of PLD in this model of metastasis breast cancer is eagerly awaiting.

Toxicology

In comparison to nonliposomal conventional doxorubicin, it is certain that the liposomal formulations of doxorubicin promote better cardiac safety. [7],[9],[10],[11],[12],[13],[14],[19],[21] The reduced cardiac toxicity had also been observed in comparison to other anthracycline-based chemotherapy. [14] Therefore, it is recommended that the liposomal formulations of doxorubicin should be used in the patients with high risk of cardiac events such as arrhythmia, congestive heart failure, and myocardial infarction. [13],[21]

Furthermore, the reduced toxicity has also been observed in terms of myelosuppression and infection in comparison to nonliposomal conventional doxorubicin. [10] However, the myelotoxicity of liposomal doxorubicin is not uncommon. [7],[12] The myelotoxic effects in association with liposomal doxorubicin include leukopenia, neutropenia, thrombocytopenia, and febrile neutropenia. [7],[9],[10],[11],[12],[13],[14],[19]

In terms of extra-myelotoxicity other than cardiotoxicity, the occurrence of Palmar-Plantar Erythrodysesthesia (commonly known as a hand-foot syndrome) is similar in both liposomal and nonliposomal formulations of doxorubicin. [9],[11],[21] Nausea and vomiting are moderate to severe in patients treated with nonliposomal doxorubicin but are usually mild in patients treated with liposomal doxorubicin. [3],[19]

As the liposomal formulations of doxorubicin undergo viability in relation to PKs, dose-dependent myelotoxicity cannot be effectively predicted. [7],[9],[10],[11],[12],[13],[14] Factors affecting the PKs of liposomal doxorubicin are likely to affect the toxicology profile of such formulations. In general, higher risk of toxicity is expected to be seen in elderly patient, immunosuppressive" and female individuals. [8] Patients with high body fat composition, particularly intraabdominal fat, are also more susceptible to experience doxorubicin-associated myelotoxicity if they are treated with liposomal doxorubicin. [12]

Under the extremely rare scenario, acute peculiar mucous reaction following administration of PLD had been reported. [29] No study had been conducted in this area as the occurrence of this reaction had not been observed prior to the case report. Hence, further study has to be carried out in this area.

Quality Of Life And Cost-Effectiveness Analysis

Although the improved survival rate with the use of liposomal doxorubicin has not been proven, it is observed that the patients receiving liposomal doxorubicin have a higher quality of life than the patients treated with nonliposomal doxorubicin in terms of pain, cognitive functioning, social functioning, and health distress. [21],[25] The improved quality of life is believed to be associated with the decreased adverse drug effects and the elevated selectivity promoted by the liposome in the liposomal formulation of doxorubicin.

However, the improved quality of life other than nausea and vomiting related to liposomal doxorubicin has not been detected in elderly patients with metastatic breast cancer. [19] This phenomenon can be explained by the deteriorated immune system of the elderly patients, resulting in a significant decrease in the CL of liposomal doxorubicin. [28] Consequently, a significant increase in AUC accounts for the dose-dependent toxicity following the administration of liposomal doxorubicin. [11]

Since the utilization of liposomal doxorubicin reduces the severity of chemotherapy-induced nausea and vomiting (CINV) in conjunction with the treatment of nonliposomal conventional doxorubicin, it is deemed to reduce the direct cost related to the CINV. As the CINV had been highlighted to be a significant cost to the National Health Service in European countries, the possibility of cost reduction is clinically significant. [17] Nonetheless, further investigation is needed to confirm the actuality of this extrapolation.

Regarding the routine cardiac surveillance prior to PLD treatment, it is believed to be unnecessary as selective cardiac surveillance will save more than 180,000 USD in 184 patients received PLD. [26] However, as PLD is 100-times more costly than conventional nonliposomal doxorubicin, it is debatable that an opportunity of saving more than 4,400,000 USD will be ignored if practicing selective cardiac surveillance. [30]

As there is a lack of updated primary sources comparing the cost-effectiveness of liposomal doxorubicin and nonliposomal conventional doxorubicin, the cost-effectiveness studies comparing liposomal doxorubicin with other nonliposomal anticancer drugs have been included. The assumption being made is that similar result will be expected in nonliposomal conventional doxorubicin in comparison to other nonliposomal anticancer drugs as they belong to the class of chemotherapy whereas liposomal doxorubicin belongs to the class of nanotherapy.

In comparison to anticancer drugs other than doxorubicin, PLD has a higher efficacy and cost than gemcitabine, the incremental cost-effectiveness ratio (ICER) observed for PLD was between €170 and €318 per QALW, which is between €8864 and €16581 per quality-adjusted life year (QALY) gained. [23] In terms of paclitaxel, PLD possesses higher efficacy and cost, with an ICER of 21,658 USD per QALY gained. [20] Overall, PLD is deemed to be cost-effective in some most countries, referring to the willingness-to-pay (WTP) threshold recommended by World Health Organization (WHO). [31] However, based on the gross domestic product stated by WHO, PLD may not be cost-effectiveness in some developing countries. [31]

Discussion And Clinical Implication

This review highlights the clinical significance of the interpatient variability associated with the use of liposomal doxorubicin. It is impacted by age, gender, race, immune status, and body fat composition of an individual treated with liposomal doxorubicin. [8],[9],[12] An important clinical concern is that most cancer patients are middle-aged or elderly, indicating a need for dose adjustment in the treatment of liposomal doxorubicin. Otherwise, the dose-dependent toxicity associated with liposomal doxorubicin cannot be extrapolated and managed. However, the effective way of individualizing the dose of liposomal doxorubicin has not been identified.

In the near future, the liposomal doxorubicin will be prescribed in more conditions such as pediatric glioma and intracranial model of breast cancer as the utilization of the liposome brings about the penetration across BBB. [15],[22] As the PK model of the liposomal doxorubicin in children remains unclear, more comprehensive precautions will be required to prevent or manage the adverse drug reaction of the liposomal doxorubicin in this population. Concerning the intracranial model of breast cancer, further studies are needed to investigate how the liposomal doxorubicin behaves in human settings. [22]

In terms of efficacy, there is limited evidence base to support the superiority of the liposomal doxorubicin compared to the nonliposomal conventional doxorubicin. [6],[7],[10],[13],[22],[24] Nevertheless, stringent precautions are recommended before choosing a formulation of doxorubicin for high-risk patients to protect against fatal cardiac events, as the reduced cardiotoxicity promoted by the liposomal doxorubicin has been confirmed. Subsequently, the clinical concern aroused is the cost-effectiveness of the routine cardiac surveillance prior to the introduction of liposomal doxorubicin. Overall, there remains a considerable controversy over the relative importance of routine cardiac surveillance in the patients accepting doxorubicin-based therapy.

Although the updated cost-effectiveness of the liposomal doxorubicin compared to nonliposomal doxorubicin remains unclear, the cost-effectiveness of liposomal doxorubicin in comparison to other chemotherapy is within the Willingness to Pay (WTP) threshold in most developed countries, so that the use of liposomal doxorubicin is deemed to be cost-effective only in this particular countries. [20],[23],[31] In healthcare settings, liposomal doxorubicin is considered to be more tolerable than nonliposomal conventional doxorubicin as regards of cardiotoxicity, myelotoxicity, nausea and vomiting with an estimation of 100 times the additional cost. Therefore, further pharmacoeconomic studies comparing liposomal and nonliposomal formulations of doxorubicin will be required to confirm the cost-effectiveness of liposomal doxorubicin.

In addition, this review reveals some limitations and weaknesses in relation to the updated evidence. The lack of blinding and allocation concealment in the randomized control trials could probably lead to a bias toward the superiority of liposomal formulation of doxorubicin compared to nonliposomal conventional doxorubicin. Another common weakness in most of the literature is the underpowered sample size. Therefore, it is identified that the sample present in the studies may not represent the whole population. Hence, larger studies are required to confirm the actuality of the results. Notwithstanding, the contamination, and co-intervention in most of the studies are well controlled, indicating that the results could be statistically and clinically significant. Further, our review did not compare the efficacy and toxicology of liposomal doxorubicin with other marketed chemotherapy, which is thought to be closely related to the current healthcare settings.

Conclusion

In summary, there remains a substantial gap in the scientific literature on the superiority of liposomal doxorubicin in relation to efficacy. While there is some experimental evidence that liposomal doxorubicin is able to increase survival rate in mice having an intracranial model of breast cancer, there is less evidence on its efficacy in healthcare settings. Current research has several limitations including the possibility of selection bias and performance bias as well as underpowered samples. However, it is confirmed that PLD and non-PLD encompass better safety profile compared to nonliposomal conventional doxorubicin in terms of cardiotoxicity and myelosuppression. However, larger interpatient variability in terms of PK is common in liposomal doxorubicin resulting in the difficulty in dose standardization. Moreover, the utilization of liposomal doxorubicin in the treatment of brain tumor will be developed in the near future. Large intervention studies in this area are likely to provide the best evidence of the efficacy of liposomal doxorubicin in increasing the survival rate in comparison to nonliposomal conventional doxorubicin. Finally, dose standardization is an urgent priority to manage the doxorubicin-induced toxicity following the administration of liposomal doxorubicin.

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